The erythropoietin (EPO) receptor mediates erythropoiesis and erythroleukemia. The interaction between EPO and its receptor on erythrocyte progenitors induces cellular proliferation and differentiation which gives rise to mature erythrocytes. EPO is clinically useful for treating anemia due to chronic renal failure, and is also being studied as a treatment for other types of anemia. Despite the importance of EPO and EPOR to human health, very little is known about their interactions or the mechanism of signal transduction. The EPO receptor is also involved in the induction of cancer. A single- site mutation on the receptor results in constitutive activation, and leads to erythroleukemia in mice, demonstrating that members of the cytokine receptor superfamily are oncogenic. There exists a second mechanism by which the EPO receptor causes disease. The interaction between the murine receptor and the glycoprotein gp55 of the Friend Spleen Focus-Forming Virus initiates a cascade of events culminating in erythroleukemia. This disease bears a number of similarities to polycythemia vera, an incurable myeloproliferative disorder characterized by increased numbers of red blood cells. The long term objective of this project is to fully characterize the molecular interactions that lead to erythropoiesis and erythroleukemia. The study in this proposal focuses on using mutational analysis and structural techniques to (a) determine the interactions between the EPO receptor and its ligand, and (b) identify residues on the extracellular domain of the receptor which are involved in signal transduction.